Novel medical device coatings

ABSTRACT

The present invention relates to coatings comprising polyethylene glycol and at least one polyphenolic polymer. In particular, the polyphenolic polymer could be selected from the group consisting of tyrosine-derived polyarylates, linear polyesteramides, dihydroxybenzoate polymers, and resorcinol-derived polymers. The coating of the present invention may also include a drug, such as an antibiotic. The coatings of the present invention are suitable for use as coatings for medical devices, such as orthopedic pins or stents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/376,790, filed Aug. 25, 2010, the disclosure of whichis hereby incorporated by reference herein in its entirety.

BACKGROUND

The incidence of infections after total joint replacement surgery hasincreased over the past decade despite the widespread use of intravenousantibiotic prophylaxis and a focus on aseptic surgical technique.Post-arthroplasty infections still occur in about 1.2% of primaryarthroplasties and 3-5% of revisions. As the demand for jointreplacements increases with the aging population, the total number ofinfections is projected to rise from 17,000 to 266,000 per year by 2030as the number of arthroplasties exceeds 3.8 million surgeries. Thetreatment of a post-arthroplasty infection is exceedingly difficult.Bacteria (especially S. aureus) form extracellular anionicpolysaccharide biofilms on implanted metallic/plastic materials thatblock penetration of immune cells and antibiotics, promoting bacterialsurvival. Once a biofilm is formed, surgical removal of all theimplanted materials is necessary. Most of these infections are caused bystaphylococcal species (about 70%) and an increasing number are due tovirulent antibiotic-resistant strains such as methicillin-resistant S.aureus (MRSA), which further complicate treatment.

The current standard of care in the U.S. to treat a chronicpost-arthroplasty infection is a two-stage procedure beginning with (1)surgical removal of all prosthetic components and bone cement,debridement of necrotic/granulation tissue, placement of anantibiotic-impregnated spacer, administration of a 6-week course ofintravenous antibiotics (during which the patient is unable to bearweight on the affected limb), and (2) revision arthroplasty after theinfection has cleared. In severe infections and refractory cases,arthrodesis, resection arthroplasty and amputation are sometimesnecessary. In the elderly, these infections result in increasedmortality. Overall, the treatment of post-arthroplasty infectioninvolves extensive medical and surgical care, prolongeddisability/rehabilitation and significantly worse outcomes. In addition,these infections represent an enormous economic burden due to additionalmedical costs and resource utilization as well as indirectly throughlost wages and productivity. These medical costs alone average $144,514(compared with $30,173 for an uncomplicated arthroplasty), whichcorrespond to an annual national healthcare burden of $8.63 billion by2015.

Most post-arthroplasty infections are thought to be caused by invadingbacteria at the time of surgery. As treatment of infected implantedmaterials is exceedingly difficult, especially due to the inherentdifficulties in treating an established biofilm, one potentialtherapeutic strategy is to focus on the prevention of infection.

One way to avoid infection is to use implantable devices that deliver adrug, such as an antibiotic, directly to the implantation site. Localdelivery of certain drugs can be more effective than traditionalsystemic routs, as certain tissues, particularly bone tissue, havelimited vascularity. Additionally, local delivery allows for a highlocal concentration while avoiding systemic side-effects.

Local delivery of a large bolus dose at the time of surgery would notprovide long term effects. While pumps to deliver drugs to a local sitemay be used in certain cases, they are not feasible in all circumstancesand can be cumbersome.

In order to achieve local, continuous delivery of a drug, medicaldevices can be coated with a drug in a manner that would allow thesustained and localized release of the drug.

Implantable medical devices can be made from various materials,including, but not limited to, metals, polymers or a combination ofdifferent materials. Metals commonly used in implantable medical devicesinclude, but are not limited to, titanium and stainless steel. Commonpolymers, include, but are not limited to, polyethylene andpolypropylene. However, due to the differences in surface energiesbetween polymers and metals, what may be a suitable coating on onematerial will not be effective on another.

While metals have surface energies of around 100, the surface energy ofa polymer is typically around 30. The relative surface energies of asurface and coating material affect the ability of the coating materialto effectively adhere to the surface. In order for a liquid (such as acoating solution) to optimally adhere to a surface, it must thoroughly“wet out” the surface to which it is to be bonded. “Wetting out” meansthat the liquid flows and covers a surface to maximize the contact areaand the attractive forces between the liquid and solid surface. For aliquid such as an adhesive or coating solution to effectively wet out asurface, the surface energy of the liquid must be as low as or lowerthan the surface energy of the substrate. Standard adhesive or coatingformulations wet out and bond to high surface energy (HSE) surfaces suchas metal or ABS plastic, but fail to bond to low surface energy (LSE)polyolefins that include polypropylene and polyethylene.

For traditional structural adhesives or coatings to bond low surfaceenergy substrates such as polyolefins, surface treatments, such asexposure to UV light or treatment with chromic acid, have been used toraise the substrate surface energy by as much as 30% to better meet theadhesive surface energy. Other strategies to modify the surfaceproperties and precisely tune interfacial interactions of materialsinclude, lithographic patterning, binary assembly, anodic oxidation,electrodeposition and chemical etching, plasma etching, laser treating,ion bombardment, UV light inducement, surfactants, chemical oxidationtreatment, polymer modification, electrospinning, electrochemicaletching, chemical vapor deposition, sol-gelprocessing, and so on.Although high quality surfaces can be fabricated by the above mentionedapproaches, these methods all have some disadvantages limiting theirfurther applications, such as the complexity of experimental setup,rigorous preparation conditions, higher energy cost and the dependenceon the specific surface chemistries. Moreover, these methods are onlysuitable for some given substrates and cannot be applied to a wide rangeof surfaces or substrates.

For example, current state of the art drug-eluting stents usually haveone to three or more layers in the coating e.g. a base layer foradhesion, a main layer for holding the drug, and sometimes a top coat toslow down the release of the drug and extend its effect. For example,the CYPHER® stent requires an initial base-layer of parylene to allowfor adhesion of the drug containing polymer. Replacing these multiplecoats with a single coating would result in more straightforwardmanufacturing.

US Patent Application No. 2007/0198040 A1 describes a bioresorbablepolymer coating on a surgical mesh as a carrier for the antimicrobialagents rifampin and minocyline. However, a coating suitable for apolypropylene mesh may not provide enough adhesion to medical devices,such as orthopedic pins, which are made of metal and/or undergosignificant manipulation and abrasion during surgical installation.

Therefore, there is a need for polymeric coatings that can provideimproved adhesion to substrates with varying surface properties.Furthermore, these coatings should also be biocompatible in order toavoid rejection; sturdy/sticky to avoid peeling off during implantation;biodegradable/resorbable so there is no long term foreign body response;capable of sustained delivery of drugs; easily tailored to delivervariety of drugs; easily tailored for coating onto different substrates;easily applied to a variety of devices by spraying; dipping or melting;and compatible with other excipients. It has been surprisinglydiscovered that a blend of certain polyphenolic polymers andpolyethylene glycol does provide such properties when coated ontomedical devices having a wide range of different surfacecharacteristics.

SUMMARY OF THE INVENTION

The present invention is directed towards an improved coating for amedical device, where the coating comprises a mixture of polyethyleneglycol, at least one polyphenolic polymer, and optionally at least onedrug.

In some embodiments, the polyethylene glycol is selected from the groupconsisting of poloxamers, PEG-3350, PEG-1000, PEG-400, or PEGs havingmodified end caps.

In some embodiments, the polyphenolic polymer is a selected from thegroup consisting of tyrosine-derived polyarylates, linearpolyesteramides, dihydroxybenzoate polymers, and resorcinol-derivedpolymers as described herein.

Suitable tyrosine-derived polyarylates include those of Formula (I):

wherein R₁ is independently selected from CH═CH or (CH₂)_(n),

n ranges from 0 to 18;

Y is selected from the group consisting of C₁-C₁₈ alkylamino, —OR′,—NHCH₂CO₂R′, —NH(CH₂)_(q)OR′, —NH(CH₂CH₂O)_(p)R′, —NH(CH₂CH₂CH₂O)_(p)R′,

q ranges from 0 to 4;

p ranges from 1 to 5000;

R′ is independently selected from the group consisting of H, C₁-C₁₈alkyl, C₂-C₁₈ alkenyl, C₈-C₁₄ alkylaryl, benzyl, and substituted benzyl;

R₂ is independently selected from the group consisting of a divalent,linear or branched, substituted or unsubstituted alkylene, alkenylene,alkynylene, arylene, alkylarylene, alkyl ether or aryl ether moietyhaving from 1 to 30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—;and —(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s))CO(R₅)_(q)—;

R₃ and R₄ are independently selected from the group consisting ofhydrogen and, a linear or branched, substituted or unsubstituted alkylhaving from 1 to 10 carbon atoms; and

R₅ is independently selected from the group consisting of a linear orbranched, lower alkylene or lower alkenylene.

Suitable linear polyesteramides comprise one or more monomer unitshaving the formula:

wherein R is —(CR₃R₄)_(a) or —CR₃═CR₄—;

R₁ is selected from the group consisting of hydrogen, a saturated orunsaturated, substituted or unsubstituted alkyl, aryl, alkylaryl oralkyl ether having from 1 to 20 carbon atoms, and—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆;

R₂ is selected from the group consisting of a divalent, linear orbranched, substituted or unsubstituted alkylene, alkenylene, alkynylene,arylene, alkylarylene, alkyl ether or aryl ether moiety having from 1 to30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—, and—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—;

R₃ and R₄ are independently selected from the group consisting ofhydrogen and a linear or branched, substituted or unsubstituted alkylhaving from 1 to 10 carbon atoms;

R₅ is independently selected from the group consisting of a linear orbranched lower alkylene or lower alkenylene group;

R₆ is independently selected from the group consisting of a linear orbranched, substituted or unsubstituted, saturated or unsaturated loweralkyl group;

where the aromatic ring of the polyesteramides have from zero to four Z₁substituents, each of which is independently selected from the groupconsisting of halide, lower alkyl, alkoxy, nitro, alkyl ether, aprotected hydroxyl group, a protected amino group and a protectedcarboxylic acid group; and

Y is selected from the group consisting of

where a is 0 to 10;

q is independently 1 to 4;

r is independently 1 to 4; and

s is independently 1 to 5000.

Suitable dihydroxybenzoate (DHB) polymers comprise one or more monomerunits having the formula:

wherein A is selected from the group consisting of C(O), C(O)—R₁—C(O),C(═N), C(O)—NH—R₁—NH—C(O) or C(S);

W is selected from the group consisting of O, NH or S;

R is selected from the group consisting of hydrogen, an ester or amideprotecting group, a leaving group, a linear or branched, substituted orunsubstituted, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyether,heteroaryl, heteroalkyl or cycloalkyl group having from 1 to 30 carbonatoms, (R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), a sugar, apharmaceutically-active moiety, and a biologically-active moiety, wherea is independently 1 to 4; b is independently 0 or 1; r is independentlyto 4; s is independently 1 to 5000;

R₁ is independently selected from the group consisting of a divalent,linear or branched, substituted or unsubstituted alkyl, alkenyl, aryl,alkylaryl, alkylene oxide or arylene oxide moiety having from 1 to 30carbon atoms, (R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), and(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r), where each a is independently 1to 4, each r is independently 1 to 4 and s is 1 to 5000;

R₂ is independently a linear or branched lower alkyl group; and

R₃ and R₄ are independently selected from the group consisting ofhydrogen and linear or branched lower alkyl group.

Suitable resorcinol-derived polymers comprise monomer units having theformula:

wherein A is selected from the group consisting of C(O), C(O)—R₁—C(O),C(═N), C(O)—NH—R₁—NH—C(O) or C(S);

R is selected from the group consisting of hydrogen, halo, a linear orbranched, substituted or unsubstituted, alkyl, alkenyl, allynyl, aryl,alkylaryl, alkoxyether, heteroaryl, heteroalkyl or cycloalkyl grouphaving from 1 to 30 carbon atoms, (R₂)_(b)C(O)OR₂,(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), a sugar, a pharmaceutically-activecompound, and a biologically-active compound, wherein each a isindependently 1-4, each b is independently 1 to 4, r is independently1-4, and each s is independently 1-5000;

R₁ is independently selected from the group consisting of a divalent,linear or branched, substituted or unsubstituted alkyl, alkenyl,alkylene oxide or arylene oxide moiety having from 1 to 30 carbon atoms,(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), or(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r), where each a is independently 1to 4, each r is independently 1 to 4 and s is 1 to 5000;

R₂ is independently linear or branched lower alkyl; and

R₃ and R₄ are independently selected from the group consisting ofhydrogen, and a linear or branched lower alkyl group.

In a particular embodiment of the invention, the coating comprises about0.1% to about 25% polyethylene glycol and about 75% to about 99.9% of apolyphenolic polymer, by weight of the combined coating.

In yet another embodiment of the invention, the coating comprises about10% to about 18% polyethylene glycol and about 72 to about 90% of apolyphenolic polymer, by weight of the combined coating.

The optional drug may be elected from the group consisting ofantimicrobial agents, anesthetics, analgesics, anti-inflammatory agents,anti-scarring agents, anti-fibrotic agents and leukotriene inhibitors.In another embodiment of the invention, the drug is an antimicrobialagent selected from the group consisting of antibiotics, antiseptics,and disinfectants. In yet another embodiment, the drug is an antibioticselected from the group consisting of rifampin, minocycline,silverlchlorhexidine, and combinations thereof. In certain embodiments,the coating comprises both rifampin and minocycline.

In some embodiments, the present invention comprises a medical devicecoated with a coating comprising a polyethylene glycol, at least onepolyphenolic polymer, and optionally at least one drug, wherein thesurface of the medical device comprises a material selected from metals,including stainless steel and titanium; organic and/or natural orsynthetic polymers including polyethylene, polylactic acid, polyglycolicacid, cellulose, and mixtures of various restorable polymers; andmaterials from a biological origin including porcine heart valves.

In yet another embodiment of the invention, the medical device is aorthopedic fixation device. In certain embodiments of the invention, theorthopedic fixation device is a screw, tack rod, pin, or plate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows stainless-steel orthopedic pins coated with P(22-27.5),P(22-27.5) and 10% PEG-1000 by weight, or P(22-27.5) and 10% PluronicL44 by weight as compared to an uncoated pin.

FIG. 2 shows the effect of sterilization on the molecular weight anddrug content of the coating.

FIG. 3 shows the cumulative release of minocycline or rifampin from thecoated pins as a function of time.

FIG. 4 shows the amount of antibiotic released at each time point.

FIG. 5 shows the zone of inhibition (“ZOI”) for various coatedsubstrates.

FIG. 6 shows the ‘stickiness’ of substrates coated with P22-27.5%blended with 10% of PEG-400, PEG-Acid, PEG-1000, or PEG-3350 as comparedto Teflon.

FIGS. 7A and 7B shows the ‘stickiness’ of substrates coated with P1012blended with 10% of PEG-400, PEG-Acid, PEG-1000, or PEG-3350 as comparedto Teflon.

FIG. 8 shows the ‘stickiness’ of substrates coated with P(DTPPGlutarate), P(MeDHB-15 DHB Glutarate), or P(TE-DG-TE-Glutarate) blendedwith 10% of PEG-400, PEG-Acid, PEG-1000, or PEG-3350 as compared toTeflon.

FIG. 9 shows a mouse surgical procedure where an implant is insertedinto a joint space.

FIG. 10A shows in vivo S. aureus bioluminescence.

FIG. 10B shows Bacterial Counts (in vivo bioluminescence).

FIG. 10C shows Total S. aureus CFUs harvested from the implant and jointtissue on Day 5.

FIG. 10D shows Correlation of in vivo bioluminescence and total CFUsharvested on Day 5.

FIG. 11A shows in vivo S. aureus bioluminescence.

FIG. 11B shows in vivo S. aureus bioluminescence representative images.

FIG. 11C shows in vivo EGFP neutrophil fluorescence.

FIG. 11D shows in vivo EGFP neutrophil fluorescence representativeimages.

FIG. 12 shows a histologic analysis of post-operative knee joints inboth infected and uninfected models.

FIG. 13 shows the formation of biofilms on metallic implants in variousmodels.

FIG. 14 provides a comparison of bacteria growth when utilizingantibiotic-polymer coated pins and uncoated pins.

DETAILED DESCRIPTION

In some embodiments, the coatings of the present invention comprise atleast one polyphenolic polymer blended with polyethylene glycol. Inother embodiments the coatings of the present invention comprise atleast one polyphenolic polymer blended with polyethylene glycol and atleast one drug.

In certain embodiments of the invention, suitable polyphenolic polymersare biodegradable polymers such as tyrosine-derived polyarylates,including those polymers described in U.S. Pat. Nos. 4,980,449;5,099,060; 5,216,115; 5,317,077; 5,587,507; 5,658,995; 5,670,602;6,048,521; 6,120,491; 6,319,492; 6,475,477; 6,602,497; 6,852,308;7,056,493; RE37,160E; and RE37,795E; as well as those described in U.S.Patent Publication Nos. 2002/0151668; 2003/0138488; 2003/0216307;200410254334; 2005/0165203; and those described in PCT Publication Nos.WO99/52962; WO 01/49249; WO 01/49311; WO 03/091337; the disclosures ofwhich are hereby incorporated by reference herein in their entirety.These patents and publications also disclose other polymers containingtyrosine-derived diphenol monomer units or other diphenol monomer units,including polyarylates, polycarbonates, polyiminocarbonates,polythiocarbonates, polyphosphonates and polyethers.

Other polyphenolic polymers suitable for use in the coatings of thepresent invention include those described in U.S. Patent PublicationNos. US 2010/0015237; US 2010/0130478; US 2010/0074940 (linearpolyesteramides from aminophenolic esters); U.S. Patent Publication No.US 2010/0129417 (dihydroxybenzoate polymers); US 2010/0167992; and US2009/0088548.

Likewise, the foregoing patents and publications describe methods formaking these polymers, some methods of which may be applicable tosynthesizing other biodegradable polymers.

Polymers

DEFINITIONS AND ABBREVIATIONS

The compounds herein described may have asymmetric (chiral) centers. Allchiral, diastereomeric, and racemic forms are included in the presentinvention. Geometric isomers of olefins and the like can also be presentin the compounds described herein, and all such stable isomers arecontemplated in the present invention.

By “stable compound” or “stable structure” is meant herein a compound ormolecule that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and for formulation into oruse as an efficacious therapeutic agent.

As used herein, unless otherwise clear from the context, “alkyl” meansboth branched- and straight-chain, saturated aliphatic hydrocarbongroups having the specified number of carbon atoms. Straight and linearare used interchangeably. As used herein “lower alkyl” means an alkylgroup having 1 to 6 carbon atoms. When substituted, the substituents caninclude halide, alkyl, alkoxy, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoroethyl, additional substituents as describedherein, and the like, compatible with the synthesis of the molecules ofthe invention.

As used herein, “alkenyl” means hydrocarbon chains of either a straightor branched configuration and one or more unsaturated carbon-carbondouble bonds, such as ethenyl, propenyl, and the like. “Lower alkenyl”is an alkenyl group having 2 to 6 carbon atoms. As used herein,“alkynyl” means hydrocarbon chains of either a straight or branchedconfiguration and one or more carbon-carbon triple bonds, such asethynyl, propynyl and the like. “Lower alkynyl” is an alkynyl grouphaving 2 to 6 carbon atoms. When the number of carbon atoms is notspecified, then alkyl, alkenyl and alkynyl refers to the respectivegroups having from 2-20 carbon atoms. Alkylene and alkenylene groups arealkyl groups and alkenyl groups, respectively, which are divalent. Whensubstituted, the substituents can include halide, lower alkyl, alkoxy,hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoroethyl,additional substituents as described herein, and the like compatiblewith the properties and synthesis of the molecules of the invention.

As used herein, “saturated or unsaturated alkyl” refers to any of analkyl group, an alkenyl group, or an alkynyl group, having any degree ofsaturation, i.e., completely saturated (as in alkyl), one or more doublebonds (as in alkenyl) or one or more triple bonds (as in alkynyl).

Examples of alkyl groups include but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,n-heptyl, n-octyl, isooctyl, nonyl, decyl, and the like; alkylene andalkenylene groups include but are not limited to, methylene, ethylene,propylenes, propenylene, butylenes, butadiene, pentene, n-hexene,isohexene, n-heptene, n-octene, isooctene, nonene, decene, and the like.Those of ordinary skill in the art are familiar with numerous linear andbranched hydrocarbon groups. Alkynyl groups include but are not limitedto ethynyl and propynyl groups.

As used herein, “aryl” means any stable 6- to 14-membered monocyclic,bicyclic or tricyclic ring, containing at least one aromatic carbonring, for example, phenyl, naphthyl, indanyl, tetrahydronaphthyl(tetralinyl) and the like. When substituted, the substituents caninclude halide, alkyl, alkoxy, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoroethyl, additional substituents as describedherein, and the like compatible with the properties and synthesis of themolecules of the invention.

As used herein, “alkylaryl” refers to a moiety in which an aryl group isattached to an alkyl group, which in turn is the attachment point of thesubstituent. For example, a benzyl ester represents an alkylaryl moietyin which the methylene attached to a phenyl ring is bonded to the oxygenof the ester. The aryl group of this moiety can optionally besubstituted in accordance with the definitions herein.

The term “substituted” as used herein means that one or more hydrogenson the designated atom are replaced with a selection from the indicatedgroups, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound. If nosubstituent is indicated then the valency is filled with a hydrogen.

The term “substituted benzyl” refers to benzyl groups substituted withone or more halogens, methoxy groups, nitro groups, alkyl groups, andthe like. Substituted benzyl groups known in the art to be suitable foruse as protecting groups for ethers and esters are included, includingbut not limited to 4-methoxybenzyl, 2-methoxybenzyl,2,4-dimethoxybenzyl, and 2-nitrobenzyl groups.

The terms “radical,” “group,” “functional group,” “moiety,” and“substituent” can be used interchangeably in some contexts and can beused together to further describe a chemical structure. For example, theterm “functional group” can refer to a chemical “group” or “radical,”which is a chemical structure variable that can be in-chain, pendantand/or terminal to the chemical structure. A functional group may besubstituted.

A “halide” or a “halo” group is a halogen atom, and includes fluoro,chloro, bromo and iodo groups.

The term “alkoxy” refers to an alkyl group having at least one oxygensubstituent represented, for example, by R—O—, where is generally analkyl group. Suitable alkoxy groups include, without limitation,methoxy, ethoxy, and propoxy.

Examples of poly(alkylene glycols) include, but are not limited to,poly(ethylene oxide)(PEG), poly(propylene glycol) (PPG),poly(tetramethylene glycol), and any derivatives, analogs, homologues,congeners, salts, copolymers and combinations thereof. Poly(alkyleneglycols) also include poloxamers (including those sold under the brandname Pluronics® as discussed herein) and those poly(alkylene glycols)having at least one terminal functional other than a hydroxyl group.

Abbreviations used herein for naming polymers and the subunits thereofinclude DBB, dihydroxybenzoic acid; Bz, benzyl; Et, ethyl; glu,glutarate; Me, methyl; PEG, polyethylene glycol; succ, suecinate; Res,resorcinol; dig, diglycolate.

Tyrosine-Based Polyarylates

In some embodiments of the invention, the polyphenolic polymers arecomprised of biodegradable tyrosine-derived diphenols co-polymerizedwith a diacid to form; it is believed, non-toxic bioerodablepolyarylates. These polymers have various structural moieties that makethem suitable for use with different substrates:

Aromatic Ring Hydrophobic Non polar Low Energy Alky chains HydrophobicNon polar Low Energy Amide groups Hydrophilic Polar High Energy Estergroups Hydrophilic Polar High Energy Acid groups Hydrophilic Polar HighEnergy Phenolic OH Hydrophilic Polar High Energy

The polyarylates of the present invention are prepared by thecondensation of a diacid with a diphenol according to the methoddescribed by U.S. Pat. No. 5,216,115, in which diphenol compounds arereacted with aliphatic or aromatic dicarboxylic acids in a carbodiimidemediated direct polyesterification using4-(dimethylamino)-pyridinium-p-toluene sulfonate (DPTS) as a catalyst.The disclosure of U.S. Pat. No. 5,216,115 is hereby incorporated byreference herein its entirety.

In certain embodiments of the invention, the coating comprises apolyarylate having repeating units with the structure of Formula I:

wherein R₁ is independently selected from the group consisting of CH═CHor (CH₂)_(n), where n ranges from 0 to 18;

Y is selected from the group consisting of C₁-C₁₈ alkylamino, —OR′,—NHCH₂CO₂R′, —NH(CH₂)_(q)OR′, —NH(CH₂CH₂O)_(p)R′, —NH(CH₂CH₂CH₂O)_(p)R′,

q is 0 to 4;

p is 1 to 5000;

R′ is independently selected from the group consisting of H, C₁-C₁₈alkyl, C₂-C₁₈ alkenyl, C₈-C₁₄ alkylaryl, benzyl, and substituted benzyl;

R₂ is independently a divalent, linear or branched, substituted orunsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene,alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms;—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—; or—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s))CO(R₅)_(q)—;

R₃ and R₄ are independently selected from the group consisting ofhydrogen and linear or branched, substituted or unsubstituted alkylhaving from 1 to 10 carbon atoms; and

R₅ is independently selected from a group consisting of a linear orbranched, lower alkylene or lower alkenylene.

The diphenol compounds may be selected from the tyrosine-deriveddiphenol monomers of U.S. Pat. Nos. 5,587,507 and 5,670,602, thedisclosures of both of which are also incorporated herein by reference.In some embodiments, the polyarylates of Formula I are prepared usingtyrosine-derived diphenol monomers having the structure of Formula II:

wherein R₁ and Y are the same as described above with respect to FormulaI.

In other embodiments of this invention, the diphenol monomers aredesaminotyrosyltyrosine carboxylic acids and esters thereof, wherein R₁is —CH₂CH₂—, which are referred to herein as DT esters. For purposes ofthe present invention, the ethyl ester (Y═OR₂; R₂=ethyl) is referred toas DTE; the benzyl ester (Y═OR₂; R₂=benzyl) is referred to as DTBn; whenY═—NH₂—CH₂—CO₂—CH₃, (glycine methyl ester linked through the amino groupof glycine) the compound is referred as DTGM; when Y═OR₂ and R₂=propylparaben the compound is referred to as DTPP, and so forth. Both U.S.Pat. Nos. 5,587,507 and 5,670,602 disclose methods by which thesemonomers may be prepared where these disclosures are hereby incorporatedherein by reference. For purposes of the present invention, thedesaminotyrosyl-tyrosine free carboxylic acid (Y═OH) is referred to asDT.

It is believed that it may not be possible to polymerize thepolyarylates having pendant free carboxylic acid groups from thecorresponding diphenols with pendant free carboxylic acid groups withoutcross-reaction of the free carboxylic acid groups with the co-monomer.Accordingly, polyarylates that are homopolymers or copolymers of benzylester diphenyl monomers, such as DTBn, may be converted to correspondingfree carboxylic acid homopolymers and copolymers through the selectiveremoval of the benzyl groups by the palladium catalyzed hydrogenolysismethod disclosed in U.S. Pat. No. 6,120,491, the disclosure of which isincorporated by reference herein. In most embodiments catalytichydrogenolysis is necessary because the lability of the polymer backboneprevents the employment of harsher hydrolysis techniques.

In particular embodiments of the invention, the dicarboxylic acids arederived from poly(alkylene oxides) such as polyethylene glycol,polypropylene glycol, polybutylene glycol, Pluronics and the like. Inspecific embodiments, the diacids are polyethylene glycol diacids.

It is believed that the polyarylates of the present invention degrade byhydrolysis into the original starting materials, i.e., thetyrosine-derived diphenols and the poly(alkylene oxide)dicarboxylicacids. The poly(alkylene oxide)dicarboxylic acids that are poly(alkyleneoxides)bis-functionalized with dicarboxylic acids further degrade to thestarting poly(alkylene oxides) and dicarboxylic acids.

The polyarylates of the present invention are believed to be highlyhydrophilic, which is advantageous for polymeric drug delivery systems.However, the hydrophilic:hydrophobic balance of the polyarylates can bevaried in several ways. The ester of the pendant chain of the diphenolcan be changed, with longer-chain ester groups increasinghydrophobicity. Increasing the molecular weight of the poly(alkyleneoxide) or increasing the number of carbons in the alkylene group of thepoly(alkylene oxide) will also increase hydrophobicity. Changing thedicarboxylic acid used to bis-functionalized the poly(alkylene oxide)will also change the hydrophilic:hydrophobic balance.

In some embodiments, the polyarylates have weight average molecularweights between about 1,000 and 500,000 daltons. In other embodiments,the polyarylates have weight average molecular weights between about3,000 and 50,000 daltons. In yetother embodiments, the polyarylates haveweight average molecular weights between about 5,000 and 15,000 daltons.Molecular weights are calculated by gel permeation chromatographyrelative to polystyrene standards in tetrahydrofuran without furthercorrection.

The molecular weights of the polyarylates can be controlled either bylimiting the reaction time or the ratios of either component. Molecularweights can also be controlled by the quantity of the carbodiimidecoupling reagent that is used. The viscosities of the polyarylates ofthe present invention can also be reduced by mixing with water to formeither an aqueous solution or emulsion of the polymer.

As used herein, DTE is the diphenol monomer desaminotyrosyl-tyrosineethyl ester; DTBn is the diphenol monomer desaminotyrosyl-tyrosinebenzyl ester; DT is the corresponding free acid form, namelydesaminotyrosyl-tyrosine. BTE is the diphenol monomer 4-hydroxy benzoicacid-tyrosyl ethyl ester; BT is the corresponding free acid form, namely4-hydroxy benzoic acid-tyrosine.

P22 is a polyarylate copolymer produced by condensation of DTE withsuccinate. P22-10, P22-15, P22-20, P22-xx, etc., each representcopolymers produced by condensation of (1) a mixture of DTE and DT usingthe indicated percentage of DT (i.e., 10, 15, 20 and xx % DT, etc.) with(2) succinate. The P22 copolymer can contain from about 0-50%, about5-50%, about 5-40%, about 1-30% or about 10-30% DT, including but notlimited to, about 1, about 2, about 5, about 10, about 15, about 20,about 25, about 27.5, about 30, about 35, about 40%, about 45% and about50% DT.

Additional suitable tyrosine-based polyarylates are copolymers ofdesaminotyrosyltyrosine (DT) and an desaminotyrosyl-tyrosyl ester (DTester), wherein the copolymer comprises from about 0.001% DT to about80% DT and the ester moiety can be a branched or unbranched alkyl,alkylaryl, or alkylene ether group having up to 18 carbon atoms, anygroup of which can, optionally have a polyalkylene oxide therein.Similarly, another group of suitable polyarylates are the same as theforegoing but the desaminotyrosyl moiety is replaced by a4-hydroxybenzoyl moiety. In particular embodiments, the DT or BTcontents include those copolymers with from about 1% to about 30%, fromabout 5% to about 30% from about 10 to about 30% DT or BT. Preferreddiacids (used informing the polyarylates) include succinate, glutarateand glycolic acid.

Additional biodegradable polymers useful for the present invention arethe biodegradable, resorbable polyarylates and polycarbonates disclosedin U.S. provisional application Ser. No. 60/733,988, filed Nov. 3, 2005and in its corresponding PCT Appln. No. PCT/US06/42944, filed Nov. 3,2006. These polymers, include, but are not limited to, BTE glutarate,DTM glutarate, DT propylamide glutarate, DT glycineamide glutarate, BTEsuccinate, BTM succinate, BTE succinate PEG, BTM succinate PEG, DTMsuccinate PEG, DTM succinate, DT N-hydroxysuccinimide succinate, DTglucosamine succinate, DT glucosamine glutarate, DT PEG ester succinate,DT PEG amide succinate, DT PEG ester glutarate and DT PEG estersuccinate.

Additionally, the polyarylate polymers used in the present invention canhave from 0.1-99.9% PEG diacid to promote the degradation process asdescribed in U.S. provisional application Ser. No. 60/733,988. Inparticular embodiments, suitable polyarylates comprise blends ofpolyarylates, or blends of other biodegradable polymers withpolyarylates.

Linear Polyesteramides

The coatings of the present invention may also comprise biodegradablepolyesteramides (PEA) polymers. These synthetic polymers comprise one ormore repeating units represented by the formula

wherein

R is selected from the group consisting of —(CR₃R₄)_(a) and —CR₃═CR₄—;

R₁ is selected from the group consisting of hydrogen and saturated orunsaturated alkyl, aryl, alkylaryl or alkyl ether having from 1 to 20carbon atoms and —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆;

R₂ is independently selected from the group consisting of a divalent,linear or branched, substituted or unsubstituted alkylene, alkenylene,alkynylene, arylene, alkylarylene, alkyl ether and aryl ether moietyhaving from 1 to 30 carbon atoms; —(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q)—;and —(R₅)_(q)CO₂(CR₃R₄)_(r)O)_(s)CO(R₅)_(q)—;

R₃ and R₄ are independently selected from the group consisting ofhydrogen and linear or branched, substituted or unsubstituted alkylgroups having from 1 to 10 carbon atoms;

R₅ is independently selected from the group consisting of a linear andbranched, lower alkylene and lower alkenylene groups;

R₆ is independently selected from the group consisting of linear andbranched, substituted or unsubstituted, saturated or unsaturated loweralkyl group;

where the aromatic ring has from zero to four Z1 substituents, each ofwhich is independently selected from the group consisting of halidelower alkyl, alkoxy, nitro, alkyl ether, a protected hydroxyl group, aprotected amino group and a protected carboxylic acid group;

Y is selected from the group consisting of

a is 0 to 10;

q is independently 1 to 4;

r is independently 1 to 4; and

s is independently 1 to 5000.

These polymers are believed to be biodegradable PEA polymers havingaminophenol units and diacid units which can be generally represented bythe formula p(-AP-X—)n where n is the actual number or the weightaverage number of repeat units in the polymer.

The aminophenols (AP) have the structure shown in Formula III:

and the diacids (X) have the structure shown in Formula IV:

When these monomeric units are polymerized under condensation conditions(or other precursors depending on the synthesis route), the resultantpolymers have backbones with both ester and amide bonds, and side chainswith ester or free acids (depending on the choice of R₁). While therepeat motif of the polymer has the structure AP-X, this simplerepresentation of the polymer does not reflect the various couplingpermutations of the aminophenol and the diacid, i.e., whether thecoupling between the aminophenol and the diacid occurs via reaction ofthe AP's amine functional group with one of the acid groups to producean amide linkage or via reaction of the AP's hydroxyl functional groupwith one of the acid groups to produce an ester linkage. Hence, the AP-Xrepeat unit can be represented by the either structure below (“repeat a”or “repeat b”, respectively).

However, this simple structural representation (-AP-X—) does not showthe relative relationship of these units to one another since theseunits can be further joined together by either an amide or ester bond.Hence, the actual structures of the polymers of the present inventionwhich contain the aminophenol and diacid moieties described hereindepend on the choice of synthetic route, the choice of coupling agentsand the selective reactivity in forming amide or ester bonds.

Accordingly, the polymers of the invention are random copolymers ofrepeats a and b or strictly alternating copolymers of repeat a, repeat bor both repeats a and b, with the particular polymer structuredetermined by the method of synthesis as described herein.

For purposes of nomenclature, random copolymers of repeats a and b, aredenominated by the simple formula p(-AP-X—), AP-X or as random abpolymers, such names being used interchangeably. Names for this polymerclass are based on these representations so that random ab polymers arenamed for the aminophenol moiety followed by the diacid moiety,regardless of the starting materials. For example, a polymer made byrandom copolymerization of tyrosine ethyl ester (TB) as the aminophenolmoiety with succinic acid as the diacid moiety is referred to as p(TEsuccinate) or TE succinate. If the diacid moiety were changed toglutaric acid, this random copolymer would be p(TE glutarate) or TEglutarate. For additional clarity or emphasis, the word random may beappended to the polymer name, e.g., TE succinate random or p(1’Esuccinate) random. If the polymer is designated without anything afterthe name, then the polymer is a random copolymer.

There are two strictly alternating copolymer classes that can beobtained from these monomeric units: (1) a linear string of a singlerepeat, either “repeat a,” thus in format (a)n or “repeat b,” thus informat (b)_(n) which are equivalent formats; or (2) a linear string ofalternating “repeat a” and “repeat b,” thus in form (ab)_(n) or(ba)_(n), which are equivalent representations for these polymers. Inall cases, n is the number of repeat units. For polymers, n is usuallycalculated from the average molecular weight of the polymer divided bythe molecular weight of the repeat unit.

For purposes of nomenclature, strictly alternating polymers of the(a)_(n) form are referred to as p(—O-AP-X—) or as alternating “a”polymers. Alternating “a” polymers occur when the reaction conditionsare such that the free amine of the aminophenol reacts first with thediacid (or other appropriate reagent) as controlled by the reactioncondition, forming an amide linkage and leaving the hydroxyl free forfurther reaction. For example, a polymer made by copolymerization oftyrosine ethyl ester (TE) as the aminophenol moiety with succinicanhydride (to provide the diacid moiety) leads to an alternating “a”polymer and is referred to herein as p(O-TE succinate) or O-TEsuccinate.

For purposes of nomenclature, polymers of the (ab), form are referred toas p(-AP-X₁-AP-X₂), p(AP-X₁-AP X₂) or as AP-X₁-AP X₂, when having a andb repeats with different diacids or as “p(-AP-X—) alternating” or asAP-X alternating, when the a and b repeats have the same diacid.

Polymers with two different diacids can be made, for example, byreacting two equivalents of an aminophenol with one equivalent of afirst diacid under conditions that favor amide bond formation andisolating the reaction product, a compound having the structureAP-X₁-AP, which is also referred to herein as a trimer because itconsists of two aminophenol units and one diacid unit. This trimer isreacted with a second diacid under polymerization conditions to producethe polymer p(-AP-X₁-AP-X₂—) if the second diacid is different from thefirst diacid, or to produce the polymer p(-AP-X—) alternating if thesecond diacid is the same as the first diacid. As an illustration, aninitial trimer made from TE and succinic acid is denominated asTE-succinate-TE. Reaction of TE-succinate-TE with glutaric acid producesthe polymer p(TE-succinate-TE glutarate), whereas reaction with succinicacid produces the polymer p(TE succinate) alternating.

Similarly, p(TE-DG-TE-glutarate) can be made from an initial trimer madefrom TE and digylcolic acid, TE-DG-TE, which is then reacted withglutaric acid to produce p(TE-DG-TE-glutarate).

The polymers of the invention also include polymers made with mixedaminophenol repeats, mixed diacid repeats and mixed trimer repeats, orany combination of such mixtures. For these complex polymers, the mixedmoiety is designated by placing a colon between the names of the twomoieties and indicating the percentage of one of the moieties. Forexample, p(TE:10TBz succinate) random is a polymer made by using amixture of 90% tyrosine ethyl ester and 10% tyrosine benzyl ester withan equimolar amount of the diacid succinic acid under random synthesisconditions. An example of a strictly alternating (ab)n polymer with amixed second diacid is p(TE-diglycolate-‘1’E10PEG-bis-succinate:adipate). This polymer is made by preparing the‘1’E-diglycolate-TE trimer and copolymerizing it with a mixture of 10%PEG-bissuccinic acid and 90% adipic acid. An example of a strictlyalternating (ab), polymer with mixed trimers isp(TE-succinate-TE:35TE-glutarate-TE succinate). This polymer is made byconducting a separate synthesis for each trimer, mixing the isolatedtrimers in the indicated ratio (65 mol % TE-succinate-TE135 mole %TE-glutarate-TE) and copolymerizing with an equimolar amount of succinicacid.

Other examples of this class of polymers can be found in U.S. PatentPublication No. 2010/0074940.

Dihydroxybenzoate and Resorcinol-Derived Polymers

The coatings of the present invention may also comprisedihydroxybenzoate (DHB) and resorcinol-derived biocompatible,biodegradable and/or resorbable polymers. These polymers are describedin detail in U.S. Patent Publication No. 2010/0129417, the disclosure ofwhich is hereby incorporated by reference herein.

The DHB-derived polymers comprise one or more monomer units representedby the formula

wherein

A is selected from the group consisting of C(O), C(O)—R₁—C(O), C(═N),C(O)—NH—R₁—NH—C(O) and C(S);

W is selected from the group consisting of O, NH, and S;

R is selected from the group consisting of hydrogen, an ester or amideprotecting group, a leaving group, a linear or branched, substituted orunsubstituted, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyether,heteroaryl, heteroalkyl and cycloalkyl group having from 1 to 30 carbonatoms, (R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), a sugar, apharmaceutically-active compound, and a biologically-active compound,wherein each a is independently 1 to 4, each b is independently 0 or 1,r is independently 1 to 4, and each s is independently 1 to 5000;

R₁ is independently selected from the group consisting of a divalent,linear or branched, substituted or unsubstituted alkyl, alkenyl, aryl,alkylaryl, alkylene oxide and arylene oxide moiety having from 1 to 30carbon atoms, (R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), or(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(a)CO(R₂)_(r), where each a is independently 1to 4, each r is independently 1 to 4 and s is 1 to 5000;

R₂ is independently selected from the group consisting of linear andbranched lower alkyl; and

R₃ and R₄ are independently selected from the group consisting ofhydrogen and linear or branched lower alkyl.

In some embodiments, the DHB-derived polymers are those in which W is O;A is C(O)—R₁—C(O); R is selected from the group consisting of hydrogen,a linear or branched, substituted or unsubstituted, alkyl, alkenyl,alkynyl, aryl, alkylaryl or alkoxyether group having from 1 to 30 carbonatoms, and (R₂)_(r)O((CR₃R₄)_(a)O)_(s)R₂)_(r); and each R₁ is,independently selected from the group consisting of a divalent, linearor branched, substituted or unsubstituted alkyl having from 1 to 30carbon atoms, (R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), or(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r).

The resorcinol-derived polymers comprise one or more monomer unitsrepresented by the formula

wherein

A is selected from the group consisting of C(O), C(O)—R₁—C(O), C(═N),C(O)—NH—R₁—NH—C(O) or C(S);

R is selected from the group consisting of hydrogen, halo, a linear orbranched, substituted or unsubstituted, alkyl, alkenyl, alkynyl, aryl,alkylaryl, alkoxyether, heteroaryl, heteroalkyl or cycloalkyl grouphaving from 1 to 30 carbon atoms, (R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), asugar, a pharmaceutically-active moiety, or a biologically-activemoiety, wherein each a is independently 1 to 4, each b is independently1 to 4, r is independently 1 to 4, and each s is independently 1 to5000.

R₁ is independently selected from the group consisting of a divalent,linear or branched, substituted or unsubstituted alkyl, alkenyl,alkylene oxide or arylene oxide moiety having from 1 to 30 carbon atoms,(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), or(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r), where each a is independently 1to 4, each r is independently 1 to 4 and s is 1 to 5000;

R₂ is independently selected from the group consisting of linear orbranched lower alkyl; and

R₃ and R₄ are independently selected from the group consisting ofhydrogen, and linear or branched lower alkyl.

Resorcinol-derived polymers include those in which A is C(O)—R₁—C(O); Ris hydrogen or a linear or branched, substituted or unsubstituted alkylgroup having from 1 to 30 carbon atoms; and each R₁ is, independentlyselected from the group consisting of a divalent, linear or branched,substituted or unsubstituted alkyl having from 1 to 30 carbon atoms,(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), or(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r).

The nomenclature associated with these polymers has a first part thatidentifies the polyphenolic moiety (DHB or resorcinol derivatives) and asecond part that identifies the A portion of the repeating unit.

If the first part of the monomer unit is an ester or amide, or asubstituent, that group is generally listed first in the abbreviations.Hence, MeDHB is the ester form, namely dihydroxybenzoate methyl ester.When a free acid is present (rather than or in addition to an ester),there is no need for an initial group. Thus, DHB is the free acid form.

The second part of the name identifies the group with which thepolyphenolic moiety is polymerized, such as the diacid, the carbonate,the iminocarbonate and the like. Hence, specific examples includepoly(DHB glutarate), poly(DHB carbonate) and the like.

If a mixture of polyphenol moieties or of copolymerized groups (such astwo diacids) are present in the polymer, then that part of the name mayinclude the designation “co” or may have a hyphen, along with anindication of percentage of one of the two moieties. For example,poly(MeDHB:10DHB-co-succinate) and poly(MeDHB-10-DT succinate) can beused interchangeably to mean a polymer made by copolymerizing a mixtureof 90% dihydroxybenzoate methyl ester and 10% dihydroxybenzoic acid withthe diacid succinic acid. An example of a mixed diacid ispoly(MeDHB-co-50:50 PEG600-bis-glutarate glutarate).

Other examples of this class of polymers can be found in U.S. PatentPublication No. 201010129417, the disclosure of which is herebyincorporated by reference herein.

In some embodiments of the invention, the polyphenolic polymer ispresent at about 80% to about 90% by weight, based on the combinedweight of the polyethylene glycol (or pluronic or similar compound) andpolyphenolic polymer. In other embodiments, the polyphenolic polymer ispresent at about 80% by combined weight. In other embodiments, thepolyphenolic polymer is present at about 81% by combined weight. Inother embodiments, the polyphenolic polymer is present at about 82% bycombined weight. In other embodiments, the polyphenolic polymer ispresent at about 83% by combined weight. In other embodiments, thepolyphenolic polymer is present at about 84% by combined weight. Inother embodiments, the polyphenolic polymer is present at about 85% bycombined weight. In other embodiments, the polyphenolic polymer ispresent at about 86% by combined weight. In other embodiments, thepolyphenolic polymer is present at about 87% by combined weight. Inother embodiments, the polyphenolic polymer is present at about 88% bycombined weight. In other embodiments, the polyphenolic polymer ispresent at about 89% by combined weight. In other embodiments, thepolyphenolic polymer is present at about 90% by combined weight.

PEG

In the coatings of the present invention, the polyphenolic polymersdescribed above can be blended with, polyethylene glycol (PEG),Pluronic® polymers/copolymers (poloxamers or nonionic triblockcopolymers composed of a central hydrophobic chain of polyoxypropyleneflanked by two hydrophilic chains of polyoxyethylene), or similarcompounds (collectively referred to herein as “PEG” or “polyethyleneglycol”). Pluronic® polymers are available from BASF (Florham Park,N.J.), and include block copolymers based on ethylene oxide and/orpropylene oxide. The PEGs utilized as part of the present invention mayhave any molecular weight and those of skill in the art will be able toselect a suitable PEG to provide for the desired outcome.

In some embodiments, the PEGs have at least one terminal functionalgroup other than a terminal hydroxyl group. For example, the PEGs mayhave at least one terminal functional group comprising an ether, forexample a methyl ether group.

Suitable PEGs include, but are not limited to, PEG-400 (a low molecularweight grade of PEG having, generally, a molecular weight between about380 and about 420 g/mol), PEG-1000 (having a molecular weight betweenabout 950 and about 1050 g/mol), and PEG-3350 (having a molecular weightbetween about 3200 and about 3500 g/mol).

PEG-Acid

In some embodiments, the PEG, Pluronic®, or similar compound is presentat about 2% to about 50% by weight, based on the combined weight of thepolyethylene glycol (or Pluronic® or similar compound) and polyphenolicpolymer, e.g., about 2% by weight, about 4% by weight, about 6% byweight, about 8% by weight, about 10% by weight, about 11% by weight,about 12% by weight, about 13% by weight, about 14% by weight, about 15%by weight, about 16% by weight, about 17% by weight, about 18% byweight, about 19% by weight, about 20% by weight, about 22% by weight,about 24% by weight, about 26% by weight, about 28% by weight, about 30%by weight, about 32% by weight, about 34% by weight, about 36% byweight, about 38% by weight, about 40% by weight, about 42% by weight,about 44% by weight, about 46% by weight, about 48% by weight, or about50% by weight.

Drugs

The presence of a drug in the coatings of the present invention isoptional. However, when a drug is present, any drug, biological agent oractive ingredient compatible with the process of depositing the coatingonto the surface of a medical device can be incorporated into coatingsof the present invention. Doses of such drugs and agents are known tothose of ordinary skill in the art. Those of skill in the art canreadily determine the amount of a particular drug to include in thecoatings on the meshes of the invention.

Examples of drugs suitable for use with the present invention includeanesthetics, antibiotics (antimicrobials), anti-inflammatory agents,fibrosis-inhibiting agents, anti-scarring agents, leukotrieneinhibitors/antagonists, cell growth inhibitors and the like, as well ascombinations thereof. As used herein, “drugs” is used to include alltypes of therapeutic agents, whether small molecules or large moleculessuch as proteins, nucleic acids and the like. The drugs of the inventioncan be used alone or in combination.

Any pharmaceutically acceptable form of the drugs of the presentinvention can be employed in the present invention, e.g., a free base ora pharmaceutically acceptable salt or ester thereof pharmaceuticallyacceptable salts, for instance, include sulfate, lactate, acetate,stearate, hydrochloride, tartrate, maleate, citrate, phosphate and thelike.

Examples of non-steroidal anti-inflammatories include, but are notlimited to, naproxen, ketoprofen, ibuprofen as well as diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; r-flurbiprofen; mefenamic; nabumetone; tolmetin, and sodiumsalts of each of the foregoing; ketorolac bromethamine; ketorolacbromethamine tromethamine; choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their D, f, and racemic isomers); and the methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid.

Examples of anesthetics include, but are not limited to, lidocaine,bupivacaine, and mepivacaine. Further examples of analgesics,anesthetics and narcotics include, but are not limited to acetaminophen,clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil,lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipraminemaleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene,hydromorphone, methadone, morphine, levorphanol, and hydrocodone. Localanesthetics have weak antibacterial properties and can play a dual rolein the prevention of acute pain and infection.

Examples of antimicrobials include, but are not limited to, triclosan,chlorhexidine, rifampin, minocycline (or other tetracyclinederivatives), vancomycin, daptomycin, gentamycin, cephalosporins and thelike. In particular embodiments the coatings contain rifampin andanother antimicrobial agent, for example a tetracycline derivative. Inanother preferred embodiment, the coatings contain a cephalosporin andanother antimicrobial agent. Preferred combinations include rifampin andminocycline, rifampin and gentamycin, and rifampin and minocycline. Asused herein, the term antibiotic and antibacterial can be usedinterchangeably with the term antimicrobial.

Further antimicrobials include aztreonam; cefotetan and its disodiumsalt; loracarbef; cefoxitin and its sodium salt; cefazolin and itssodium salt; cefaclor; ceflibuten and its sodium salt; ceftizoxime;ceftizoxime sodium salt; cefoperazone and its sodium salt; cefuroximeand its sodium salt; cefuroxime axetil; cefprozil; ceftazidime;cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodiumsalt; cephalexin; cefamandole nafate; cefepime and its hydrochloride,sulfate, and phosphate salt; cefdinir and its sodium salt; ceftriaxoneand its sodium salt; cefixime and its sodium salt; cefpodoxime proxetil;meropenem and its sodium salt; imipenem and its sodium salt; cilastatinand its sodium salt; azithromycin; clarithromycin; dirithromycin;erythromycin and hydrochloride, sulfate, or phosphate saltsethylsuccinate, and stearate forms thereof; clindamycin; clindamycinhydrochloride, sulfate, or phosphate salt; lincomycin and hydrochloride,sulfate, or phosphate salt thereof; tobramycin and its hydrochloride,sulfate, or phosphate salt; streptomycin and its hydrochloride, sulfate,or phosphate salt; vancomycin and its hydrochloride, sulfate, orphosphate salt; neomycin and its hydrochloride, sulfate, or phosphatesalt; acetyl sulfisoxazole; colistimethate and its sodium salt;quinupristin; dalfopristin; amoxicillin; ampicillin and its sodium salt;clavulanic acid and its sodium or potassium salt; penicillin G;penicillin G benzathine, or procaine salt; penicillin G sodium orpotassium salt; carbenicillin and its disodium or indanyl disodium salt;piperacillin and its sodium salt; ticarcillin and its disodium salt;sulbactam and its sodium salt; moxifloxacin; ciprofloxacin; ofloxacin;levofloxacins; norfloxacin; gatifloxacin; trovafloxacin mesylate;alatrofloxacin mesylate; trimethoprim; sulfamethoxazole; demeclocyclineand its hydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; minocycline and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt; andclarithromycin.

Examples of antifungals include amphotericin B; pyrimethamine;flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafinand its hydrochloride, sulfate, or phosphate salt; ketoconazole;micronazole; clotrimazole; econazole; ciclopirox; naftifine; anditraconazole.

Other drugs that can be incorporated into the coatings on the meshpouches of the invention include, but are not limited to, keflex,acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin,daunomycin, plumbagin, atropine, quinine, digoxin, quinidine,biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,cyclosporins, 5-flurouracil and the like.

Examples of anti-inflammatory compound include, but are not limited to,anecortive acetate; tetrahydrocortisol,4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione and its -21-acetatesalt; 11-epicortisol; 17.alpha.-hydroxyprogesterone;tetrahydrocortexolone; cortisona; cortisone acetate; hydrocortisone;hydrocortisone acetate; fludrocortisone; fludrocortisone acetate;fludrocortisone phosphate; prednisone; prednisolone; prednisolone sodiumphosphate; methylprednisolone; methylprednisolone acetate;methylprednisolone, sodium succinate; triamcinolone;triamcinolone-16,21-diacetate; triamcinolone acetonide and its-21-acetate, -21-disodium phosphate, and -21-hemisuccinate forms;triameinolone benetonide; triamcinolone hexacetonide; fluocinolone andfluocinolone acetate; dexamethasone and its -21-acetate,-21-(3,3-dimethylbutyrate), -21-phosphate disodium salt,-21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide.

Examples of leukotriene inhibitors/antagonists include, but are notlimited to, leukotriene receptor antagonists such as acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

Another useful drug that can be incorporated into the coatings of theinvention is sodium 2-mercaptoethane sulfonate (Mesna). Mesna has beenshown to diminish myofibroblast formation in animal studies of capsularcontracture with breast implants [Ajmal et al. (2003) Plast. Reconstr.Surg. 112:1455-1461] and may thus act as an anti-fibrosis agent.

Those of ordinary skill in the art will appreciate that any of theforegoing disclosed drugs can be used in combination with or mixed withcoatings of the present invention.

In some embodiments, the present invention comprises polyethyleneglycol, a polyphenolic polymer, and rifampin. In other embodiments, thepresent invention comprises polyethylene glycol, a polyphenolic polymer,and minocycline. In yet other embodiments, the present inventioncomprises polyethylene glycol, a polyphenolic polymer, and rifampin andminocycline.

In some embodiments, at least one drug is present at about 20% to about70% of the combined weight of the polyethylene glycol (or pluronic orsimilar compound), the polyphenolic polymer, and the drug, e.g. about20% by weight, about 25% by weight, about 30% by weight, about 35% byweight, about 40% by weight, about 45% by weight, about 50% by weight,about 55% by weight, about 60% by weight, about 65% by weight, or about70% weight.

In other embodiments, wherein at least one drug is present at about 20%to about 70% of the combined weight of the polyethylene glycol (orpluronic or similar compound), the polyphenolic polymer, and the drug,the polyethylene glycol (or pluronic or similar compound) is present atabout 3% to about 16% of the combined weight of the polyethylene glycol,the polyphenolic polymer, and the drug, e.g about 3% by weight, about 4%by weight, about 5% by weight, about 6% by weight, about 7% by weight,about 8% by weight, about 9% by weight, about 10% by weight, about 11%by weight, about 12% by weight, about 13% by weight, about 14% byweight, about 15% be weight, or about 16% by weight.

In particular embodiments of the invention wherein at least one drug ispresent at about 20% to about 70% of the combined weight of thepolyethylene glycol (or pluronic or similar compound), the polyphenolicpolymer, and the drug, the polyphenolic polymer is present at about 20%to about 75% of the of the combined weight of the polyethylene glycol,the polyphenolic polymer, and the drug, e.g. about 20% by weight, about25% by weight, about 30% by weight, about 35% by weight, about 40% byweight, about 45% by weight, about 50% by weight, about 55% by weight,about 60% by weight, about 65% by weight, about 70% by weight or about75% by weight.

Medical Devices

The coatings of the present invention can be used to coat a variety ofdifferent types of medical devices including implantable prostheses usedto reconstruct, reinforce, bridge, replace, repair, support, stabilize,position or strengthen any soft tissue defect.

Suitable medical devices are known in the art and may include a devicehaving any shape, size, and function. Suitable medical devices may beconstructed from any material known in the art and suitable for theparticular end use sought.

In some embodiments, the medical devices comprise a material selectedfrom a metal including stainless steel and titanium. In otherembodiments, the medical device comprises an organic material and/or anatural or synthetic polymer, including polyethylene, polylactic acids,polyglycolic acids, and cellulose. For example, one polymer which may beutilized is available from MAST Biosurgery, and which is particularlyuseful for hard tissue (bone) and soft tissue applications, and whichcomprises Polylactide, which is a copolymer of 70:30Poly(L-lactide-co-D,L-lactide). Other bioresorable polymers areavailable from Boehringer Ingelheim, and include the Resomer® family ofpolylactide-based copolymers. In yet other embodiments, the medicaldevice is comprises of a material from biological origin, such asmaterials from porcine origin (e.g. porcine heart valves). In otherembodiments, the medical devices may be comprised of AlloDerm®Regenerative Tissue Matrix or Strattice™ Reconstructive Tissue Matrix,both of which are available from LifeCell.

Prostheses comprising the coating of the present invention may be usedto repair soft tissue defects including hernias, such as, but notlimited to inguinal, femoral, umbilical, abdominal, incisional,intramuscular, diaphragmatic, abdomino-thoracic and thoracic hernias.

The coated prostheses can also be used for structural reinforcement formuscle flaps, to provide vascular integrity, for ligamentrepair/replacement and for organ support/positioning/repositioning suchas done with a bladder sling, a breast lift, or an organ bag/wrap. Theprostheses can be used in reconstruction procedures involving softtissue such as an orthopaedic graft support/stabilization, as supportsfor reconstructive surgical grafts and as supports for bone fractures.The prostheses are generally meshes, membranes or patches, and includewoven or non-woven meshes and the like.

Additionally, the coatings of the present invention can be used to coatwound closure adjuncts, such as staples, sutures, tacks, rings, screws,and the like. Likewise, the coatings may provide a barrier function,preferably a temporary biodegradable barrier, which prevents ormitigates contact or adhesion between a substrate (e.g. medical device)and surrounding materials or tissue.

In some embodiments, the coatings of the present invention are capableof conforming to flexible and/or deformable substrates (e.g. collapsiblestents, sutures, and the like), preferably without damaging the coatingor altering the release of the optional drug from the coating.Similarly, the coating can act to stiffen a device, including adeformable substrate, into a predetermined shape. It is believed that asthe coating biodegrades, the stiffness imparted may lesion and thedevice may assume a second, different shape or stiffness.

The coatings of the present invention can also be used to coat mesheswhich are formed into or to form pouches, coverings, pockets and thelike for implantable medical devices. Such implantable medical devicesinclude, but are not limited to cardiac rhythm management devices suchas a pacemaker, a defibrillator, a pulse generator as well as otherimplantable devices such as implantable access systems,neurostimulators, spinal cord stimulators, breast implants or any otherimplantable medical device. The coverings, pouches, pockets and the likehence can serve to secure those devices in position, provide painrelief, inhibit scarring or fibrosis, inhibit or prevent bacterialgrowth or infection (or, more particularly, prevent microbialcolonization of a substrate of bacteria), and deliver other drugs to thesite of implantation.

In some embodiments, the coated devices may be used to prevent, treat ormitigate bacterial colonization. In some embodiments, the coatingcomprises an antimicrobial agent, such that the antimicrobial agent maybe eluted over time. In some embodiments, the coating comprisesminocycline, rifampin, or a mixture of minocycline and rifampin. In someembodiments, the antimicrobial agent is eluted from the coating overtime. In other embodiments, the antimicrobial agent is eluted over aperiod of at least 24 hours. In yet other embodiments, the cumulativerelease of antimicrobial agent is at least about 30% over 24 hours. Inyet further embodiments, the cumulative release of antimicrobial agentis at least about 40% over 24 hours. In yet other embodiments, thecumulative release of antimicrobial agent is at least about 50% over 25hours. In yet further embodiments, at least about 80% of theantimicrobial agent is released after 3 days.

The coatings of the present invention can also be used in conjunctionwith any implantable or insertable medical devices which has atemporary, or some time-limited therapeutic need as well as those withpermanent function (such as joint replacements).

Other examples of medical devices on which the coating compositionsdescribed herein can be coated include, but are not limited to catheters(e.g., renal or vascular catheters such as balloon catheters), guidewires, balloons, filters (e.g., vena cava filters), stents (includingcoronary vascular stents, cerebral, urethral, ureteral, biliary,tracheal, gastrointestinal and esophageal stents), stent grafts,cerebral aneurysm filler coils (including Guglilmi detachable coils andmetal coils), vascular grafts, myocardial plugs, femoral plugs, patches,pacemakers and pacemaker leads, heart valves, vascular valves, biopsydevices, patches for delivery of therapeutic agent to intact skin andbroken skin (including wounds); tissue engineering scaffolds forcartilage, bone, skin and other in vivo tissue regeneration; sutures,suture anchors, anastomosis clips and rings, tissue staples and ligatingclips at surgical sites; orthopedic fixation devices such asinterference screws in the ankle, knee, and hand areas, tacks forligament attachment and meniscal repair, rods and pins for fracturefixation, screws and plates for cranionaxillofacial repair; dentaldevices such as void fillers following tooth extraction andguided-tissue-regeneration membrane films following periodontal surgery;and various coated substrates that are implanted or inserted into thebody.

In yet other embodiments, the coatings may be applied to the dressingsused in negative pressure wound therapy. Dressings used in such atherapy include foams (open and closed cell foams), meshes, gauzes, orother textiles having a textured or dimpled wound contact surface. Insome embodiments, suitable dressings include V.A.C. Simplace Dressings,V.A.C. Granufoam Bridge Dressings, V.A.C. Abdominal Dressing System, andV.A.C. WhiteFoam Dressings, available from Kinetic Concepts, Inc. (SanAntonio, Tex.). In other embodiments, suitable dressings include thosefrom Smith & Nephew and sold under the brand names RENASYS-F Foam andRENASYS-G Gauze (St. Petersburg, Fla.). In yet other embodiments,suitable dressings include those available from Prospea (Fort Worth,Tex.).

The coating may be applied to any surface of the negative pressure woundtherapy dressing. In some embodiments, the coating at least partiallycovers the surface of the dressing which is in contact with the wound,incision, etc. of the subject. In some embodiments, the coating appliedto the negative pressure wound therapy dressing includes at least onedrug. In other embodiments, the coating applied to the negative pressurewound therapy dressing includes at least one antimicrobial compound. Inyet other embodiments, the coating applied to the negative pressurewound therapy dressing includes rifampin and minocycline. It is believedthat the drug included in any coating applied to a dressing may beeluted over a predetermined time period such that effective amounts ofthe drug are administered to the wound or incision of the subject. It isfurther believed that the inclusion of an antimicrobial compound in thedressing coating could prevent, treat, or mitigate any infectionspresent in the wound or incision.

Accordingly, the present invention provides methods of treating adisorder or condition in a patient comprising implanting a medicaldevice or a medical device assembly coated with a coating composition ofthe present invention, e.g., as a coating, in conjunction with acovering or as the complete or partial device, by implanting the devicein a patient, and particularly for disorders and conditions such as acardiovascular disorder, a neurological disorder, a hernia orhernia-related disorder, an ophthalmic condition, or anatomical repair,reconstruction, replacement or augmentation.

In some embodiments, the method is used to implant a stent to treatatherosclerosis, thrombosis, restenosis, periodontitis, hemorrhage,vascular dissection or perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, claudication, anastomotic proliferationfor vein and artificial grafts, bile duct obstruction, ureterobstruction, tumor obstruction, or combinations thereof

In other embodiments, the coating compositions of the present inventioncan be used as part of a method to implant a medical device for localdelivery of drugs, such as nerve growth factors to stimulate nerveregeneration or chemotherapeutic agents to treat cancer. In yet anotherembodiment of the invention, coated punctual plugs can be used forocular delivery.

In other embodiments, the coating compositions of the present inventioncan be used as part of a method to implant a surgical mesh toreconstruct, reinforce, bridge, replace, repair, support, stabilize,position or strengthen any soft tissue defect, including a hernia.

In yet other embodiments, the coating compositions of the presentinvention can be used as part of a method to implant a medical deviceassembly such as a CRM in a covering or pouch, a neurostimulator in apouch or covering, or a breast implant in a pouch or covering.

Application

The compositions of the present invention may be applied to the surface(interior or exterior) of a medical device by any suitable techniqueknown in the art. In a particular embodiment of the invention thecoating composition is sprayed onto the surface of the device. In yetanother embodiment of the invention, the device is dipped into thecoating composition.

In a certain embodiment of the invention, the coating is cured afterapplication by any suitable technique known in the art, including, butnot limited to, exposure to ultraviolet radiation, electron beams,microwave beams or heat. In a particular embodiment of the invention,the polymer coating is cured at about 40° to about 70° C. under vacuum.

In another embodiment of the invention, the coating is cast into asheet, this sheet is then placed on to the device, and the coating isadhered to the device by curing. In a particular embodiment of theinvention, this curing can take place at about 40° to about 70° C. undervacuum.

In a further embodiment of the invention, the coating is cast into atube, the device is then placed in the tube, and the coating is adheredto the device by curing. In a certain embodiment of the invention, thiscuring can take place at about 40° to about 70° C. under vacuum.

This approach of first manufacturing films comprising the compositionsof the present invention, then applying such films to a device orsubstrate can be advantageous in simplifying quality control (e.g., byallowing the manufacture of a single lot of film which can be qualifiedby a single quality control test, whereas direct coating of various abatches of devices may require multiple quality control tests), or byallowing the coating to be custom-fitted to the device during a medicalprocedure. The degree of stickiness of the coating can also be adjustedby modifying the type of PEG polymer used in the composition. Forexample, stickier coatings are provided by the use of PEG, whereasreduced levels of stickiness can be obtained using copolymers ofpolyethylene oxide/polypropylene oxide, such as PLURONIC polymers. Lesssticky coatings can be useful in situations where there may be a need toremove the coating. In a particular embodiment of the invention, whereinthe coating comprises PLURONIC, an applied coating can be removed and/orreplaced.

In yet another embodiment of the invention, an orthopedic pin can becoated with the coating of the present invention and then be cut to theappropriate size for insertion.

In some embodiments, the medical device is at least partially covered bythe coatings of the present invention. In other embodiments, at leastabout 25% of the surface of the medical device is covered by thecoatings of the present invention. In yet other embodiments, at leastabout 30% of the surface of the medical device is covered by thecoatings of the present invention. In yet further embodiments, at leastabout 40% of the surface of the medical device is covered by thecoatings of the present invention.

Medical Applications

As discussed above infections after total joint arthroplasty represent aclinically devastating complication. These infections are exceedingdifficult to treat because the implanted materials provide avascularsurfaces to which bacteria adhere and form biofilms, which block thepenetration of immune cells and antibiotics. A medical device coatedwith an antibiotic impregnated coating containing minocycline andrifampin effectively reduces infection, decreases inflammation andprevents biofilm formation on implants.

The antibiotic-impregnated bioresorbable tyrosine-derived polymercoatings of the present invention, such as P22-27.5 blended with PEG400,which slowly elute minocycline and rifampin, are clinically effective inreducing bacterial load, preventing the infection, decreasing neutrophilinfiltration/inflammation and preventing biofilm formation on theimplants.

A previous study in a rabbit intramedullary screw S. aureusosteomyelitis model found that minocycline and rifampin sprayed onto theimplant without an elution polymer was only partially effective inpreventing colonization of the implant and infection of the bone. Thepolymer coating of the present invention is more effective at preventingbacterial infection, and therefore the subsequent complications, thanpreviously used methods which do not allow for continuous, extendedrelease of drugs after implantation. These results suggest that thiscoating can be used to prevent infections associated with the use oforthopedic implants. It will be appreciated by those skilled in the artthat various omissions, additions and modifications may be made to theinvention described above without departing from the scope of theinvention, and all such modifications and changes are intended to fallwithin the scope of the invention, as defined by the appended claims.All references, patents, patent applications or other documents citedare herein incorporated by reference in their entirety for all purposes.

Examples

The coatings are described based on the polymer content of the coating.For example, a coating wherein 90% of the polymer content is P(22-27.5)and 10% is PEG-1000 and would be described as “P(22-27.5):10% PEG-1000”.

I. Coating

A. Preparation of Coating Solution without Drug

P22-27.5 (0.85 g) and PEG 1000 (0.15 g) were weighted into a 20 mL cleanamber vial. 3.5 mL of dichloromethane and 1.5 mL of methanol were added,then the mixture was shaken to dissolve the components using a vortexshaker. The mixture was filtered and the solution was transferred into aclean 7 mL scintillation vial using a polypropylene syringe fitted witha 1 micron syringe filter. The vial was capped and let stand at least 5minutes before use.

B. Preparation of Coating Solution with Drug

P22-27.5 (0.85 g), PEG-1000 (0.15 g), Rifampin (0.40 g) and MinoeyclineHCL (0.4 g) were weighted into a 20 mL clean amber vial. 3.5 mLdichloromethane and 1.5 mL methanol were added and then the mixture wasshaken to dissolve the components using a vortex shaker. When thesolution was clear, it was filtered into a clean 7 mL scintillation vialusing a polypropylene syringe fitted with a 1 micron syringe filter. Thevial was capped and let stand for at least 5 minutes before use.

C. Dipping Procedure for 1 Inch Pin

A minimum portion (about 2 mm) of the pin was inserted into a 200 μLpipette tip. The exposed side of the pin was manually dipped into theprepared solution (at least ¾ of the pin surface should be covered bythe solution). The pin was slowly raised from the solution and left onthe pipette tip until it dried. The pin was carefully removed from thepipette tip, reversed, and the coated side was inserted into the pipettetip. The uncoated portion of the pin was again inserted into theprepared solution. Slowly the pin was raised and left on the 200 pLpipette tip until it was dry. If more coating needed to be added ontothe cut end of the pin, the procedure could be repeated. The pins weredried under vacuum until acceptable solvent levels were obtained. Thepins were stored in tightly sealed containers at ˜15 C.

D. Automated Dipping Procedure

A minimum portion (about 2 mm) of the pin was inserted into a 200 μLpipette tip as described above. The pipette was screwed onto an aluminumstem made for the diptech coating machine. The stem was inserted intothe platform of diptech coating machine. The machine was started andcyclic dipping of the pin into the prepared solution was commenced.

E. Spraying Procedure:

P22-27.5 (1.48 g), Rifampin (0.26 g) and Minocycline (0.26 g) wereweighed into a 250 mL of amber jar. 180 mL of dichloromethane and 20 mLof methanol were added and then dissolved using a magnetic stirrer. 50mL of solution were drawn into an airtight syringe which was connectedto a Sonotek sprayer. The syringe was placed on a syringe pump which hada designated pushing speed. Then the pin was inserted into the 200 [μLpipette tip as described above, and the pipette was affixed to amechanical stirrer. When the stirrer started to rotate, the sprayer wasstarted and the syringe pump to coat the pin.

F. Coating Polyethylene by Casting and Curing at 70° C.

Weigh P22-27.5 (0.85 g) and PEG 1000 (0.15 g) were weighed into a 20 mLclean amber vial. 9 mL of dichloromethane and 1 mL methanol were addedand shaken to dissolve using a vortex shaker. The solution was pouredonto a leveled TEFLON coated glass sheet. The wet film was covered andallowed to dry under ambient conditions. After the film was dry, it wastransferred onto the polyethylene sheet that is to be coated. The filmwas cured at 70° C. under vacuum until the required residual solventlevel was obtained.

Similar methods could be used to formulate coatings comprising variousamounts and types of polyphenolic polymers, PEGs and drugs. Curing isalso possible at other temperatures, including at bout 40° C.

G. Coating Orthopedic Pins

Stainless-steel orthopedic pins were coated as described above withP(22-27.5), P(22-27.5) and 10% PEG-1000 by weight, or P(22-27.5) and 10%Pluronic L44 by weight. FIG. 1 shows an uncoated pin and the threecoated pins.

II. Properties

A. Sterilization

Medical devices coated with P(22-27.5), 10% PEG-1000 by weight, orP(22-27.5):10% Pluronic L44 blend were sterilized with gammairradiation. FIG. 2 shows that the sterilization had a minimal effect onthe coating as measured by molecular weight and drug content.

B. Release of Minocycline and Rifampin from Coated Pins

Orthopedic pins coated with P(22-27.5), P(22-27.5):10% PEG-1000 byweight, or P(22-27.5):10% Pluronic L44 in combination with minocyclin orrifampin were prepared as described above. The pins were placed in PBSat 37° C. and a sample withdrawn periodically for determination ofminocyclin or rifampin content by HPLC. FIG. 3 shows the cumulativerelease of minocyclin or rifampin into PBS from the coated pins as afunction of time. FIG. 4 shows the amount of antibiotic released at eachtime point.

C. Zone of Inhibition Studies

The ZOI for antibiotic coated meshes was determined according-to theKirby-Bauer method. Staphylococcus epiderrnidis or Staphylococcus aureuswere inoculated into Triplicate Soy Broth (TSB) from a stock culture andincubated at 37° C. until the turbidity reached McFarland #0.5 standard(1-2 hours). Plates were prepared by streaking the bacteria onto onMueller-Hinton II agar (MHA) three times, each time swabbing the platefrom left to right to cover the entire plate and rotating the platebetween swabbing to change direction of the streaks.

A pre-cut piece (1-2 cm²) of spray-coated mesh was firmly pressed intothe center of pre-warmed Mueller Hinton II agar plates and incubated at37° C. Pieces were transferred every 24 h to fresh, pre-warmed MuellerHinton II agar plates using sterile forceps. The distance from thesample to the outer edge of the inhibition zone was measured every 24 hand is reported on the bottom row in Table 2 and 3 for each sample. Thetop row for each sample represents difference between the diameter ofthe ZOI and the diagonal of the mesh. Table 2 shows the ZOI results formeshes placed on S. epidermidis lawns and Table 3 shows the ZOI resultsfor meshes placed on S. aureus lawns. Additionally, three pieces wereremoved every 24 h for analysis of residual minocycline and rifampin.

FIG. 5 shows the total ZOI on S. aureus for meshes with coated with P(22-27.5), P (22-27.5):10% PEG-1000 by weight, or P(22-27.5):10%Pluronic L44 in combination with minocyclin or rifampin.

D. P(DTE Succinate) with Varying Percentages of Free Carboxylate

Devices of titanium, stainless steal, ultra-high-molecular-weightpolyethylene and very-high-molecular-weight polyethylene were coatedwith P-22 (p(DTE succinate)), P22-10 (p(DTE co 10% DT succinate)), orP22-15 (p(DTE co 10% DT succinate)) blended with 10% of PEG-400,PEG-400-Acid, PEG-1000, PEG-3350 and Pluronic L44 as described above.

FIG. 6 shows the ‘stickiness’ of the coated substrate as compared toTeflon. According to the data, there is at least about a 6-fold increasein stickiness for metal substrates and about a 4-fold increase forpolyethylene substrates.

E. P(DTH Adipate)

Devices of titanium, stainless steal, ultra-high-molecular-weightpolyethylene and very-high-molecular-weight polyethylene were coatedwith P64 (p(DTH adipate)) or P(DThexyl adipate)) blended with 10% ofPEG-400, PEG-Acid, PEG-1000, or PEG 3350 as described above.

FIG. 7 a shows the ‘stickiness’ of the coated substrate as compared toTeflon. According to the data, there is about a 3-6-fold increase instickiness for metal substrates and about a 3- to 4-fold increase forpolyethylene substrates.

F. P (DTdodecyl dodecanoate)

Devices of titanium, stainless steal, ultra-high-molecular-weightpolyethylene and very-high-molecular-weight polyethylene were coatedwith P1012 (p(DTD DD) or p(DTdodecyl dodecanoate)) blended with 10% ofPEG-400, PEG-Acid, PEG-1000, or PEG 3350 as described above.

FIG. 7 b shows the ‘stickiness’ of the coated substrate as compared toTeflon. According to the data, there is about a 5-fold increase instickiness for metal substrates and about a 2- to 4-fold increase forpolyethylene substrates. This shows that even a polymer with a lowersurface energy, such as p1012, shows an increase in the stickiness evenon a low energy surface such as the polyethylenes.

G. P(DTPP Glutarate), P(MeDHB-15 DHB Glutarate), andP(TE-DG-TE-Glutarate) Coatings

Devices of titanium, stainless steal, ultra-high-molecular-weightpolyethylene and very-high-molecular-weight polyethylene were coatedwith p(DTPP Glutarate), p(MeDHB-15 DHB Glutarate), orp(TE-DG-TE-Glutarate) blended with 10% of PEG-400, PEG-Acid, PEG-1000,or PEG-3350 as described above.

FIG. 8 shows the ‘stickiness’ of the coated substrate as compared toTeflon. According to the data, there is about a 5- to 7-fold increase instickiness for metal substrates and about a 3- to 4-fold increase forpolyethylene substrates.

III. Implantation of a Coated Orthopedic Pin

S. aureus Bioluminescent Strain

The bioluminescent S. aureus SH1000 strain, ALC2906, which contained theshuttle plasmid pSK236 with the penicillin-binding protein 2 (pbp2)promoter fused to the luxABCDE reporter cassette from Photorhabduslumninescens, was used in all experiments. This S. aureus strainnaturally emitted bioluminescent signals from live, activelymetabolizing bacteria in all stages of the S. aureus life cycle.

Preparation of S. aureus for Inoculation into the Joint Space

S. aureus bioluminescent strain ALC2906 has a chloramphenicol resistanceselection marker and chloramphenicol (10 sg/ml; Sigma-Aldrich) wassupplemented to all cultures. S. aureus was streaked onto tryptic soyagar plates (tryptic soy broth [TSB] plus 1.5% bacto agar [BDBiosciences]) and grown at 37° C. overnight. Single colonies of S.aureus were cultured in TSB and grown overnight at 37° C. in a shakingincubator (240 rpm) (MaxQ 4450; Thermo). Mid-logarithmic phase bacteriawere obtained after a 2 h subculture of a 1150 dilution of the overnightculture. Bacterial cells were pelleted, resuspended and washed 3× inPBS. Bacterial concentrations were estimated by measuring the absorbanceat 600 nm (A6oo; Biomate 3 [Thermo]). Colony forming units were verifiedafter overnight culture of plates.

Mice

12-week old male C57BL/6 wildtype mice were used (Jackson Laboratories).In some experiments, 12-week old male LysEGFP mice, a geneticallyengineered mouse line on a C57BL/6 background possessinggreen-fluorescent myeloid cells (mostly neutrophils) as a consequence of‘knockin’ of enhanced green fluorescence protein (EGFP) into thelysozyme M gene, were used.

Mouse Surgical Procedures

Mice were anesthetized via inhalation isoflurane (2%). The surgicalprocedure was modified from previous work. A skin incision was made overthe right knee (FIG. 9A). The distal right femur was accessed through amedial parapatellar arthrotomy with lateral displacement of thequadriceps-patellar complex (FIG. 9B). After locating the femoralintercondylar notch (FIG. 9B), the femoral intramedullary canal wasmanually reamed with a 25 gauge needle (FIG. 9C). An orthopaedic-gradestainless steel Kirschner (K)-wire (diameter 0.6 mm) (Synthes) wassurgically placed in a retrograde fashion and cut with 1 mm protrudinginto the joint space (FIG. 9D). An inoculum of S. aureus in 2 μl ofnormal saline was pipetted into the joint space containing the cut endof the implant (FIG. 9E). The quadriceps-patellar complex was reduced tothe midline (FIG. 9F) and the surgical site was closed with Dexon 5-0sutures (FIG. 9G). A representative radiograph demonstrates the positionof the implant with good intramedually fixation of the stem andprominence of the cut surface in the joint (FIG. 9H). Buprenorphine (0.1mg/kg) was administered subcutaneously every 12 hours as an analgesicfor the duration of the experiment.

Quantification of In Vivo S. aureus (In Vivo Bioluminescence Imaging andColony Forming Units [CFUs])

Mice were anesthetized via inhalation of isoflurane (2%) and in vivobioluminescence imaging was performed by using the Xenogen in vivoimaging system (Xenogen IVIS®; Caliper Life Sciences). Data arepresented on color scale overlaid on a grayscale photograph of mice andquantified as maximum flux (photons per second (s) per cm per steradian(sr) [p/s/cm/sr]) within a circular region of interest (1×10³ pixels) byusing Living Image® software (Xenogen). To confirm that thebioluminescence signals corresponded to the bacterial burden in vivo,bacteria adherent to the implants were quantified by detaching thebacteria from the implant by sonication in 1 ml 0.3% Tween-80 in TSB for10 minutes followed by vortexing for 5 minutes as previously described.In addition, bacteria in the joint tissue were confii toed byhomogenizing bone and joint tissue (Pro200® Series homogenizer; ProScientific). The number of bacterial CFUs that were adherent to theimplant and in the joint tissue was determined by counting CFUs afterovernight culture of plates and was expressed as total CPUs harvestedfrom the implant and joint tissue.

Quantification of Neutrophil Recruitment to the Infected Post-OperativeJoint (In Vivo Fluorescence Imaging)

To obtain a measurement of neutrophil infiltration, LysEGFP mice wereused. After in vivo bioluminescence imaging, in vivo fluorescenceimaging was performed by using the Xenogen IVIS® (Caliper LifeSciences). EGFP-expressing neutrophils within the post-operative sitewere visualized by using the GFP filter for excitation (445-490 nm) andemission (515-575 nm) at an exposure time of 0.5 seconds. Data arepresented on color scale overlaid on a grayscale photograph of mice andquantified as total flux (photons/s) within a circular region ofinterest (1×10³ pixels) by using Living Image® software (Xenogen).

Histologic Analysis

Mice were euthanized via inhalation carbon dioxide and joint specimenswere fixed in formalin (10%) overnight. Specimens were decalcified byincubation in Decalcifier II® solution (Surgipath) for 6 h and specimenswere processed and embedded in paraffin. Sagittal sections of 4 μmthickness were cut and then were stained with hematoxylin and eosin(H&E) and Gram stain.

Variable-Pressure Scanning Electron Microscopy

A field emission variable pressure scanning electron microscope (FE-SEMZeiss Supra VP40) was used to obtain a digital image of the cut end ofthe implants. Conductive graphite glue was used to position the pins ona graphite stub. Pressure in the microscope chamber was maintained at 25Pa, which allowed the examination of the implant surface without theneed of sputter coating. Secondary and in-lens detectors were used toreveal the topographical characteristics of the surface. Examination ofthe implant occurred at regular intervals by tilting the pin between −4and 10 degrees and rotating it every 30 degrees for a total of 360degrees.

Coating of Metallic Implants with an Antibiotic-ImpregnatedBioresorbable Polymer

A bioresorbable polymer impregnated with rifampin and minocycline wasused. To coat the stainless steel K-wire implants with thisantibiotic-impregnated polymer, K-wires were hand-dipped in a mixture ofbioresorbable tyrosine-derived polyesteramide (P22-27.5), PEG400,rifampin and minocycline and methylene chloride as described in ExampleI. Vehicle coating consisted of bioresorbable tyrosine-derivedpolyesteramide, PEG400 and methylene chloride only (no antibiotic). Thecoated pins were heat dried for at least 12 h until residual solvent wasless than 600 ppm, stored at −15° C. and sterilized by gammairradiation. Three different formulations were generated (Coatings A, Band C) with the following approximate antibiotic concentrations: CoatingA: 32.5 μg/mm³ of rifampin and 36.1 μg/mm³ of minocycline; Coating B:46.1 μg/mm³ of rifampin and 47.7 μg/mm³ of minocycline; and Coating C:97.4 μg/mm³ of rifampin and 104.2 μg/mm³ of minocycline. The coatingswere repeatedly dipped until the thickness of Coating A and Coating Bwere ˜40-45 μm whereas and Coating C was ˜80-90 μm. Thus, Coatings A andB would elute at the same rate whereas Coating C would elute slowerbecause it had double the coating thickness.

Statistical Analysis

Data were compared by using a Student's t-test (two-tailed). All dataare expressed as mean±standard error of the mean (sem) where indicated.Values of p<0.05, p<0.01 and p<0.001 were considered statisticallysignificant.

In Vivo Bioluminescence Imaging to Measure the Bacterial Burden inReal-Time

To model a post-arthroplasty infection, a orthopaedic-grade K-wire(Synthes, Inc., West Chester, Pa.) was surgically placed into the femurwith the cut end protruding into knee joint and an inoculum of S. aureuswas pipetted into the joint space before closure (FIG. 9). To measurethe bacterial burden within the infected post-operative joints inreal-time, we used a bioluminescent S. aureus strain (SH1000) thatnaturally emits lights from live, ATP-producing bacteria at all stagesof the S. aureus life cycle. The bacterial burden was subsequentlymeasured on post-operative days 0, 1, 3, 5, 7 and 10 in anesthetizedmice in real-time by using the Xenogen in vivo imaging system (XenogenIVIS®; Caliper Life Sciences).

To determine the optimal bacterial inoculum to produce a chronic implantinfection, C57BL/6 mice were inoculated with increasing logarithmicconcentrations of S. aureus (5×10², 5×10³ and 5×10⁴ CFUs/2 μl). Duringthe first 5 days after the inoculation, mice that received 5×10³ or5×10⁴ CFUs had 20- to 50-fold higher bioluminescence signals thanuninfected mice (FIG. 10A, B). Clinically, both of these groups of micedeveloped marked inflammation as characterized by increased swelling anddecreased mobility of the affected leg and were euthanized onpost-operative day 5. Thus, inocula of 5×10³ or 5×10⁴ CFUs of S. aureusinduced markedly high bioluminescent signals and produced clinical signsof infection that was consistent with an acute purulent joint infection.In contrast, mice that received an inoculum of 5×10² CFUs developedsigns of infection in the affected leg that were only minimallydifferent than uninfected mice. These mice had up to 6- to 8-fold higherbioluminescence signals than the background levels of uninfected controlmice at all post-operative days through day 10 (FIG. 10A, B). The mildclinical findings combined with the low level of bacterialbioluminescence allowed us to follow the infection in the mice thatreceived the inoculum of 5×10² CFUs for at least 10 days, which moreclosely resembled a chronic and persistent infection. Thus, the inoculumof 5×10² CFUs was used in all subsequent experiments.

To confirm that the in vivo bioluminescence signals accuratelyrepresented the bacterial burden in vivo, traditional bacterial countswere performed on post-operative day 5 from bacteria adherent to theimplant and present in the joint tissue (FIG. 10C). Mice that wereinoculated with 5×10⁴, 5×10³ and 5×10⁵ CFUs had a total bacterial burdenex vivo of 8.3×14⁵, 1×10⁵ and 2.4×10⁴ CFUs, respectively (FIG. 10C). Inaddition, the in vivo bioluminescent signals correlated with thecorresponding ex vivo bacterial CFUs (correlation coefficient ofdetermination: R² 0.9873; FIG. 10D), suggesting that the in vivobioluminescence signals at least through day 5 provided an approximationof the actual bacterial burden in vivo. However, since the bacterialstrain used had the lux genes in a plasmid that is maintained in vitrounder chloramphenicol selection, the plasmid is likely lost during thein vivo infection over time. In broth culture without selection, theplasmid was stable for the first 3 days in vitro with greater than 97%of bacteria still containing the plasmid whereas only 53%, 38% and 21%of the bacteria still contained the plasmid on days 5, 7 and 10,respectively (data not shown). Thus, although the bioluminescent signalsobtained with this strain provide an approximation of the bacterialburden in vivo, it is likely an underestimate of the actual bacterialburden, especially at later time points.

In Vivo Fluorescence Imaging to Measure Neutrophil Infiltration inReal-Time

The degree of inflammation within the post-operative knee joints wasmeasured by quantifying neutrophil infiltration, a key correlate forinflammation and infection. This was accomplished by using in vivofluorescence imaging of LysEGFP mice, a genetically engineered mousestrain that possesses green-fluorescent neutrophils. The bioluminesce ntS. aureus strain infected into the knee joints of LysEGFP mice enabledsimultaneous measu.

ement of both bacterial burden and neutrophil infiltration onpost-operative days 0, 1, 3, 5, 7 and 10 (FIG. 11). Similar to C57B/16mice in FIG. 2, S. aureus (5×10² CFUs)-infected LysEGFP mice developedbioluminescence signals that were up to 8-fold higher than thebackground levels of uninfected control mice through day 10 (FIG. 11A).In addition, the S. aureus-infected LysEGFP mice had 20-40% higherEGFP-neutrophil fluorescent signals than uninfected control mice on allpost-operative days 1 to 10 (FIG. 11B). This degree of neutrophilrecruitment, confirms our clinical observations that the inoculum of5×10² CFUs produced a low-grade inflammatory response, suggesting thatEGFP-neutrophil fluorescence provides a quantifiable measurement of theclinical inflammation observed in our model.

Histologic Analysis of Post-Operative Knee Joints

To determine the location of the inflammatory infiltrate and bacterialinoculum within the infected post-operative joints, histologic sectionswere harvested from S. aureus-inoculated (5×10² CFUs) and uninfectedcontrol mice on post-operative day 1 (FIG. 12). Mice inoculated with S.aureus had increased neutrophils in the joint tissue as seen inhematoxylin & eosin (H&E) stained sections. In addition, Gram-positive(blue-staining) bacteria could be readily detected in areas ofinflammatory cells. In contrast, uninfected control mice that only hadthe surgical implant placed had minimal neutrophil infiltration and nobacteria were detected by Gram-stain. These histologic findingscorroborate our in vivo bioluminescence and fluorescence imaging datademonstrating that the inoculum of 5×10² CFUs of S. aureus inducedneutrophil infiltration and bacterial proliferation in the joint tissuein the area of the implant.

Detection of Biofilm Formation on the Metallic Implants

To evaluate whether biofilm formation occurred on the implants in ourmouse model, implants were harvested from euthanized mice onpost-operative days 7 and 14 (FIG. 13). To evaluate biofilm formation,we used variable-pressure scanning electron microscopy (VP-SEM), whichallows for visualization of biologic samples in their natural state, asthere is no need to coat them with a conductive film required fortraditional SEM. Thus, VP-SEM enabled the visualization of biofilms onthe implants without typical artifacts (dehydration, collapse,distortion, shrinkage, condensation, and aggregation) associated withconventional SEMs that require fixation and sputter coating. Miceinoculated with S. aureus had prominent biofilm formation on the cut endof the implants harvested on 7 and 14 post-operative days. In contrast,uninfected mice, which did not have any bacterial inoculation at thetime of surgery, had no detectable biofilm formation and the visualizedmetallic implant surface was virtually identical to implants prior tosurgery (Day 0). Thus, the bacteria infected the joint tissue (FIG. 13)and also formed a biofilm on the implant, which is consistent withbiofilm formation that occurs in post-arthroplasty infections inpatients.

A Novel Antibiotic-Impregnated Implant Coating to Treat S. aureusPost-Operative Joint Infection

This mouse model was employed to determine the efficacy of abioresorbable polymer impregnated with rifampin and minocycline inpreventing the development of an infection in the joint. Stainless steelK-wires were coated by three coating formulations (Coatings A, B and C),which contained increasing concentrations of the antibiotics, and onevehicle control coating (no antibiotic) (FIG. 14A). In addition,Coatings A and B had the same thickness and would elute the antibioticsat a similar rate whereas Coating C was double the thickness and wouldelute slower.

These antibiotic-coated implants were surgically placed into the distalfemurs of LysEGFP mice and the knee joint space was inoculated with5×10² CFUs of S. aureus. In vivo imaging was performed on post-operativedays 0, 1, 3, 5, 7 and 10 as in FIG. 11. Coatings B and C resulted inbioluminescence signals that were highest at the time of inoculation andwere reduced to background levels by day 3 (FIG. 14B). Coating Aresulted in bioluminescence signals that were less than the vehiclealone but did increase between 0-3 days before decreasing to backgroundlevels by day 7. As expected, the vehicle control coating, whichcontained no antibiotics, did not inhibit bacterial growth and resultedin bioluminescent signals that were up to 20-fold higher than theinitial inoculurn and up to 50-fold higher than the two most effectiveantibiotic-impregnated implant coatings (Coatings B and C). Thus, theantibiotic-impregnated coatings substantially reduced the bacterialburden and prevented infection in post-operative joints as measured byin vivo bioluminescence imaging. Since Coating A resulted in somebacterial growth, whereas no growth was detected with Coatings B or C,it is likely that both the drug concentration and elution ratecontributed to the efficacy of these coatings.

The antibiotic-eluting coated implants also substantially reducedclinical signs of inflammation. Mice with Coatings B and C ambulatedwith notably less guarding of the operative leg than mice withvehicle-coated implants. To obtain a quantifiable measurement of theinfection-induced inflammatory response, in vivo fluorescence ofEGFP-neutrophils was measured in these LysEGFP mice (FIG. 14C). CoatingsB and C, which were most effective in reducing bacterial burden, hadEGFP-neutrophil fluorescent signals that were reduced to backgroundlevels (i.e. no detectable inflammation) by post-operative day 5. Thesedata demonstrate that antibiotic-impregnated implant coatings markedlyreduced the infection-induced neutrophil recruitment and inflammation ina concentration- and elution-dependent fashion.

To determine whether the antibiotic-impregnated implant coatings had anyimpact on biofilm formation, the implants were harvested from mice onpost-operative day 7 and biofilm formation was evaluated by VP-SEM (FIG.14D). All three antibiotic-impregnated implant coatings (A, B and C)prevented biofilm formation on the cut surface of the pin within theknee joint. In contrast, the vehicle coated pin had readily detectablebiofilm formation.

1-3. (canceled)
 4. The medical device of claim 22, wherein the linearpolyesteramide comprises monomer units having the formula:

wherein R is —(CR₃R₄)_(a)— or —CR₃═CR₄—; R₁ is selected from the groupconsisting of hydrogen and a saturated or unsaturated alkyl, aryl,alkylaryl or alkyl ether having from 1 to 20 carbon atoms; or—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)—R₆; R₂ is independently selected from thegroup consisting of a divalent, linear or branched, substituted orunsubstituted alkylene, alkenylene, alkynylene, arylene, alkylarylene,alkyl ether or aryl ether moiety having from 1 to 30 carbon atoms;—(R₅)_(q)O((CR₃R₄)_(r)O)_(s)(R₅)_(q), and—(R₅)_(q)CO₂((CR₃R₄)_(r)O)_(s)CO(R₅)_(q); R₃ and R₄ are independentlyselected from the group consisting of hydrogen and a linear or branched,substituted or unsubstituted alkyl group having between 1 and 10 carbonatoms; R₅ is independently a linear or branched, lower alkylene or loweralkenylene group; R₆ is independently selected from the group consistingof a linear or branched, substituted or unsubstituted, saturated orunsaturated lower alkyl; the aromatic ring has from zero to four Z₁substituents, each of which is independently selected from the groupconsisting of halide, lower alkyl, alkoxy, nitro, alkyl ether, aprotected hydroxyl group, a protected amino group and a protectedcarboxylic acid group; Y is selected from

a is 0 to 10; q is independently 1 to 4; r is independently 1 to 4; ands is independently 1 to
 5000. 5-6. (canceled)
 7. The medical device ofclaim 22, wherein the polyethylene glycol is selected from the groupconsisting of PEG-3350, PEG-1000, and PEG-400. 8-11. (canceled)
 12. Themedical device of claim 22, wherein the coating further comprisesmicocycline and rifampin. 13-16. (canceled)
 17. The medical device ofclaim 22, wherein the coating comprises about 20% to about 70% of atleast one drug, based on the combined weight of the drug, polyethyleneglycol and polyphenolic polymer, wherein the at least one drug comprisesrifampin and minocycline. 18-21. (canceled)
 22. A medical devicecomprising a coating comprising polyethylene glycol and a polyphenolicpolymer, the polyphenolic polymer comprising a linear polyesteramide.23. The medical device of claim 22, wherein the medical device iscomprised of a material selected from the group consisting of a metal,an organic material, a natural or synthetic polymer or copolymer, and amaterial of biological origin.
 24. The medical device of claim 22,wherein a thickness of the coating ranges from 10 μm to about 250 μm.25. (canceled)
 26. The medical device of claim 22, wherein the coatingfurther comprises an antimicrobial agent.
 27. (canceled)
 28. The medicaldevice of claim 26, wherein at least about 30% to about 50% of theantimicrobial agent is eluted from the coating after about 24 hours.29-30. (canceled)
 31. The medical device of claim 26, wherein at leastabout 80% of the antimicrobial agent is eluted from the coating withinabout 3 days.
 32. The medical device of claim 22, wherein the medicaldevice is an orthopedic fixation device.
 33. The medical device of claim22, wherein the orthopedic fixation device is a screw, tack rod, pin, orplate.
 34. The medical device of claim 22, wherein the medical device isa mesh, pouch, or covering.
 35. The medical device of claim 22, whereinthe medical device is a dressing used in negative pressure woundtherapy. 36-41. (canceled)
 42. The medical device of claim 22, whereinthe medical device comprises a material selected from metals, organicnatural or synthetic polymers, and materials from a biological origin,wherein the metals include stainless steel and titanium, the organicnatural or synthetic polymers include polyethylene, polylactic acid,polyglycolic acid, cellulose, and mixtures of various restorablepolymers, and the material from the biological origin includes porcineheart valves.
 43. The medical device of claim 22, wherein the medicaldevice is configured for use for structural reinforcement for muscleflaps, to provide vascular integrity for ligament repair/replacement orfor organ support/positioning/repositioning.
 44. The medical device ofclaim 22, wherein the medical device is configured for use inreconstruction procedures involving soft tissue including orthopaedicgraft support or stabilization.
 45. The medical device of claim 22,wherein the medical device is configured for use in bone fractures. 46.The medical device of claim 22, wherein the medical device comprises adeformable substrate, and the coating is configured to biodegrade suchthat the coating stiffens or changes a shape of the medical device asthe coating biodegrades.
 47. The medical device of claim 22, wherein themedical device is selected from a group consisting of implantable accesssystems, neurostimulators, spinal cord stimulators, breast implants,biopsy devices and patches for delivery of therapeutic agent to intactskin and broken skin.